ABSTRACT Biobehavioral Studies of Cardiovascular Disease (PO1-HL040962) This Program Project (P01) continuation application focuses on the human brain substrates of behavioral and socio-environmental influences on cardiovascular disease (CVD) risk in midlife adults. Proposed are 3 Projects that are conceptually cross-linked and supported by 3 Core Units. Collaborative investigators represent multiple disciplines, including psychology, neuroscience, biophysics, medicine, psychoneuroimmunology, epidemiology, machine learning, bioinformatics, and statistics. Project 1 aims to elucidate functional and structural brain phenotypes that predict the multiyear progression of preclinical vascular disease and dysfunction, with a focus on neural circuitries for visceral control that coordinate autonomic, neuroendocrine, hemodynamic, and immune physiology with stress- and emotion-related behavioral processes. Project 2 aims to establish whether functional characteristics of these visceral control circuits moderate the influences of stress-related environmental exposures on the progression of preclinical vascular disease and dysfunction, tracking individuals' behavior and cardiovascular physiology in daily life to test a novel neuro-diathesis model of CVD risk. Project 2 also tests for the first time whether daily life physical activity associates with daily life stress physiology through its effects neural circuits for visceral control. Project 3 aims extend those of the other Projects by elucidating the neural and peripheral processes linking physical activity with physiological and psychophysiological markers of CVD risk (including daily life affect and stress physiology) using an experimental intervention methodology. These P01 aims are unique in cardiovascular behavioral medicine, and they will be pursued in the context of multi-component data collection efforts that satisfy all project-specific aims. As a result, the P01 will create new opportunities for integrative and translational science on the human neurobiology of CVD risk that cuts across multiple methods and levels of analysis. Helping to advance its parent field, the P01 will generate and disseminate original and expansive public-domain resources and tools to the broader scientific and clinical communities through comprehensive data and software sharing and educational objectives. Enabling a precise focus on early CVD etiology, the study cohorts comprise nearly 900 midlife adults without clinically apparent CVD, and study methods will include novel combinations of neuroimaging, ecological momentary assessments of experienced environments, ambulatory hemodynamic monitoring, autonomic, neuroendocrine, immune, and vascular assessments, laboratory clinical evaluations, hetero-method health behavior assessments, and arterial imaging. The 3 Core Units of this P01 provide for synergy and inter-project coordination by administrative, data management and participant accrual services; measurement and instrumentation support; and direction in cutting-edge bio-statistical and data-intensive (machine learning) analyses. The present application thus represents a thematic continuation and next- generation extension of translational neurobiological research on CVD by this P01, which was initiated in 1988.